JHM virus (JHMV)infection induces an acute inflammatory response restricted to the CNS which controls viral replication. However, it fails to fully clear virus, thereby setting the stage for a persistent CNS infection. Chronic JHMV infection is associated with persisting viral antigen and viral RNA in conjunction with ongoing demyelination. T cells play a distinct role in both viral clearance during acute infection as well as contributing to demyelination during chronic infection. Thus, rapid T cell infiltration during acute disease is crucial to controlling virus replication in order to limit subsequent immune mediated pathogenesis. The mechanisms which govern the trafficking of inflammatory cells into the CNS during acute viral induced encephalomyelitis, are relatively unknown. The goals of this project are to identify the mechanisms governing inflammatory cell entry into the CNS. Aim 1 investigates the role of IFN-alpha/beta in mediating CNS inflammation. IFN-alpha/betaR / mice will be compared to wt mice to determine the influence of IFN-alpha/beta in inducing pro and anti-inflammatory genes, including cytokines, matrix metalloproteinases (MMPs) and tissue inhibiters of MMPs (TIMPs). The kinetics and quantity" of inflammatory cell recruitment reveal the roles of IFN-alpha/beta in shaping both the innate and adaptive CNS responses to viral infection. Definition of the mechanisms of IFN-alpha/beta anti-viral activity are determined via analysis of mice deficient in the two major IFN induced anti-viral pathways. Aim 2 examines the contribution of neutrophils to regulating both the loss of blood brain barrier integrity and in shaping the overall inflammatory response within the CNS. Transient depletion of neutrophils results in dramatic reduction in CNS recruitment of inflammatory cells. CXCL2-/- mice, defective in neutrophil trafficking, will be used to characterize the proinflammatory role of neutrophils. JHMV infection is associated with induction of MMP-9 protein, a protease involved in breakdown of basement membranes. The factors which mediates initial neutrophil infiltration will be examined via infection of MMP-9-/- mice. Aim 3 investigates a novel model of impaired intra-parenchymal inflammatory cell trafficking. Infection of mice doubly deficient in perforin and IFN-gamma (PKO/GKO) results in accumulation of inflammatory cells in the subarachnoid and perivascutar areas. By contrast, infection of these mice following reconstitution with CD8+ T cells from normal donors, allows trafficking of the inflammatory cells into the CNS parenchyma. Infection of PKO/GKO mice is associated with increased expression of the MMP inhibitor TIMP-1. We will test the hypothesis that unregulated virus growth increases expression of TIMP-1, preventing MMP mediated leukocyte migration through the CNS parenchyma.